DISTRIBUTION TO THE BRAIN AND PROTEIN-BINDING OF 3'-SUBSTITUTED AND 5-SUBSTITUTED 2',3'-DIDEOXYURIDINE DERIVATIVES, STUDIED BY MICRODIALYSIS

The aim of this study was to investigate a series of 3' and 5-substitu ted 2',3'-dideoxyuridine derivatives (ddUD) with respect to plasma pro tein binding, half-life and distribution across the blood-brain barrie r in the rat. The microdialysis technique was used to study protein bi nding in human plasma (in vitro), and to sample the extracellular spac e of rats with microdialysis probes implanted into the striatum of the brain and the gastrocnemic muscle (in vivo). The compounds were analy sed by HPLC with UV-detection. The octanol/water partition coefficient s of the ddUD varied from 0.08-0.84. The protein binding of the ddUDs was approximately 80%. After s.c. administration (25 or 50 mg kg(-1)), the brain and muscle extracellular levels differed; brain levels were 0.18-0.36 of peripheral (muscle) concentrations. A multivariate analy sis, which included data on zidovudine, alovudine and thymidine, demon strated a relationship between the physicochemical and some of the pha rmacokinetic properties of uridine analogues. The analysis shows that half-life and protein binding increases with decreasing pK(a). However , penetration to the brain is not correlated with the partition into o ctanol. it is concluded that the transport to the brain is not primari ly dependent upon passive diffusion over a lipophilic barrier but, rat her, to other chemical properties of the ddUDs. This is suggestive of a specific transport mechanism, e.g. the thymidine carrier.